Stress-induced TDP-43 nuclear condensation causes splicing loss of function and STMN2 depletion

Cell Reports, Journal Year: 2024, Volume and Issue: 43(7), P. 114421 - 114421

Published: June 27, 2024

TDP-43 protein is dysregulated in several neurodegenerative diseases, which often have a multifactorial nature and may extrinsic stressors as "second hit." undergoes reversible nuclear condensation stressed cells including neurons. Here, we demonstrate that stress-inducible condensates are RNA-depleted, non-liquid assemblies distinct from the known bodies. Their formation requires oligomerization ATP inhibited by RNA. Using confocal nanoscanning assay, find amyotrophic lateral sclerosis (ALS)-linked mutations alter stress-induced changing its affinity to liquid-like ribonucleoprotein assemblies. Stress-induced transiently inactivates TDP-43, leading loss of interaction with binding partners function splicing. Splicing changes especially prominent persisting for STMN2 RNA, becomes rapidly depleted early during stress. Our results point pathological nucleus support therapeutic modulation stress response ALS.

Language: Английский

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TDP43 autoregulation gives rise to dominant negative isoforms that are tightly controlled by transcriptional and post-translational mechanisms

Cell Reports, Journal Year: 2025, Volume and Issue: 44(1), P. 115113 - 115113

Published: Jan. 1, 2025

Highlights•Short (s)TDP43 isoforms are created as a by-product of TDP43 autoregulation•sTDP43 is strictly regulated by NMD, the proteasome, and autophagy•sTDP43 potent inhibitor splicing activitySummaryThe nuclear RNA-binding protein integrally involved in pathogenesis amyotrophic lateral sclerosis (ALS) frontotemporal lobar degeneration (FTLD). Previous studies uncovered N-terminal that predominantly cytosolic localization, prone to aggregation, enriched susceptible spinal motor neurons. In healthy cells, however, these shortened difficult detect comparison full-length (fl)TDP43, raising questions regarding their origin selective regulation. Here, we show sTDP43 autoregulation cleared nonsense-mediated RNA decay (NMD). sTDP43-encoding transcripts escape NMD rapidly degraded post-translationally via proteasome macroautophagy. Circumventing regulatory mechanisms overexpressing results neurodegeneration oligomerization impairment flTDP43 activity, addition RNA-binding-dependent gain-of-function toxicity. Collectively, highlight endogenous tightly regulate expression underscore consequences aberrant accumulation disease.Graphical abstract

Language: Английский

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Multi-functional role of apolipoprotein E in neurodegenerative diseases

Frontiers in Aging Neuroscience, Journal Year: 2025, Volume and Issue: 17

Published: Jan. 29, 2025

Genetic diversity in the apolipoprotein E (ApoE) gene has been identified as major susceptibility genetic risk factor for sporadic Alzheimer’s disease (SAD). Specifically, ApoEε4 allele is a significant SAD, while ApoEε2 provides protection compared to more common ApoEε3 allele. This review discusses role of ApoE AD and other neurodegenerative disorders. ApoE, cholesterol transport protein, influences several pathways involved neurodegeneration, particularly AD. Beyond its established amyloid β -protein (Aβ) metabolism deposition, also impacts tau pathology, microglial response The aims provide an updated overview ApoE’s diverse roles, emphasizing involvement Aβ clearance through receptors. It covers influence diseases like Parkinson’s (PD), amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), Huntington’s (HD), vascular dementia (VD), multiple (MS). New research highlights interaction between presenilin (PS), suggesting connections familial (FAD) SAD. explores protective effects mutations against ApoE4-induced tauopathy, neuroinflammation. insights from this comprehensive update could indeed lead new therapeutic strategies diseases.

Language: Английский

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Long non‐coding RNAs as key regulators of neurodegenerative protein aggregation

Alzheimer s & Dementia, Journal Year: 2025, Volume and Issue: 21(2)

Published: Feb. 1, 2025

Abstract The characteristic events in neurodegenerative diseases (NDDs) encompass protein misfolding, aggregation, accumulation, and their related cellular dysfunction, synaptic function loss. While distinct proteins are implicated the pathological processes of different NDDs, process misfolding aggregation remains notably similar across various conditions. Specifically, undergo into beta‐folded (β‐folded) conformation, resulting formation insoluble amyloid proteins. Despite advancements comprehending certain facets this intricate remain incompletely elucidated. In recent years, concept that long non‐coding RNAs (lncRNAs) contribute to has gained recognition. LncRNAs influence aggregates by facilitating overexpression through regulation gene transcription translation, inhibiting degradation via lysosomal autophagic pathways, targeting aberrant modifications phase transitions A better understanding relationship between lncRNAs is an important step dissecting underlying molecular mechanisms will discovery new therapeutic targets strategies. Highlights NDDs marked leading dysfunction loss function. being involved β‐folded conformations forming consistent role attention, as they regulate inhibit degradation, target modifications. Understanding link crucial for uncovering developing targets.

Language: Английский

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Structural insights and milestones in TDP-43 research: A comprehensive review of its pathological and therapeutic advances

International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: unknown, P. 141677 - 141677

Published: March 1, 2025

Transactive response (TAR) DNA-binding protein 43 (TDP-43) is a critical RNA/DNA-binding involved in various cellular processes, including RNA splicing, transcription regulation, and stability. Mislocalization aggregation of TDP-43 the cytoplasm are key features pathogenesis several neurodegenerative diseases, amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD). This review provides comprehensive retrospective prospective analysis research, highlighting structural insights, significant milestones, evolving understanding its physiological pathological functions. We delineate five major stages from initial discovery as hallmark neurodegeneration to recent advances liquid-liquid phase separation (LLPS) behavior interactions with processes. Furthermore, we assess therapeutic strategies targeting pathology, categorizing approaches into direct indirect interventions, alongside modulating aberrant LLPS. propose that future research will focus on three areas: polymorphisms for disease-specific therapeutics, exploring dual temporal-spatial modulation TDP-43, advancing nano-therapy. More importantly, emphasize importance TDP-43's functional repertoire at mesoscale, which bridges molecular functions broader offers foundational framework development.

Language: Английский

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Amyotrophic lateral sclerosis caused by TARDBP mutations: from genetics to TDP-43 proteinopathy

The Lancet Neurology, Journal Year: 2025, Volume and Issue: 24(5), P. 456 - 470

Published: April 16, 2025

Language: Английский

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RNA-binding properties orchestrate TDP-43 homeostasis through condensate formation in vivo

Nucleic Acids Research, Journal Year: 2024, Volume and Issue: 52(9), P. 5301 - 5319

Published: Feb. 21, 2024

Insoluble cytoplasmic aggregate formation of the RNA-binding protein TDP-43 is a major hallmark neurodegenerative diseases including Amyotrophic Lateral Sclerosis. localizes predominantly in nucleus, arranging itself into dynamic condensates through liquid-liquid phase separation (LLPS). Mutations and post-translational modifications can alter condensation properties TDP-43, contributing to transition liquid-like biomolecular solid-like aggregates. However, date it has been challenge study dynamics this process vivo. We demonstrate live imaging that human undergoes nuclear spinal motor neurons living animal. deficiencies as well lead aberrant altered compartmentalization. Single-molecule tracking revealed an mobility profile for deficient TDP-43. Overall, these results provide critically needed vivo characterization condensation, important regulatory mechanism accessibility, identify molecular how functional be regulated.

Language: Английский

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In vivo diagnosis of TDP-43 proteinopathies: in search of biomarkers of clinical use

Translational Neurodegeneration, Journal Year: 2024, Volume and Issue: 13(1)

Published: June 3, 2024

TDP-43 proteinopathies are a heterogeneous group of neurodegenerative disorders that share the presence aberrant, misfolded and mislocalized deposits protein TDP-43, as in case amyotrophic lateral sclerosis some, but not all, pathological variants frontotemporal dementia. In recent years, many other diseases have been reported to primary or secondary proteinopathy, such Alzheimer's disease, Huntington's disease recently described limbic-predominant age-related encephalopathy, highlighting need for new accurate methods early detection proteinopathy help on stratification patients with overlapping clinical diagnosis. Currently, remains post-mortem pathologic Although main aim is determine central nervous system (CNS), ubiquitous expression biofluids cells outside CNS facilitates use accessible target tissues might reflect potential alterations brain. this review, we describe developments proteinopathies, their implications diagnosis future treatments.

Language: Английский

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A patient-derived amyotrophic lateral sclerosis blood-brain barrier model for focused ultrasound-mediated anti-TDP-43 antibody delivery

Fluids and Barriers of the CNS, Journal Year: 2024, Volume and Issue: 21(1)

Published: Aug. 13, 2024

Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disorder with minimally effective treatment options. An important hurdle in ALS drug development the non-invasive therapeutic access to motor cortex currently limited by presence of blood-brain barrier (BBB). Focused ultrasound and microbubble (FUS

Language: Английский

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Emerging of Ultrafine Membraneless Organelles as the Missing Piece of Nanostress: Mechanism of Biogenesis and Implications at Multilevels

ACS Nano, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 30, 2025

Understanding the interaction between nanomaterials and cellular structures is crucial for nanoparticle applications in biomedicine. We have identified a subtype of stress granules, called nanomaterial-provoked granules (NSGs), induced by gold nanorods (AuNRs). These NSGs differ from traditional SGs their physical properties biological functions. Uptake AuNRs causes reactive oxygen species accumulation protein misfolding cell, leading to NSG formation. Physically, gel-like core liquid-like shell, influenced positively HSP70 negatively HSP90 ubiquitin-proteasome system. promote assembly interacting with G3BP1, reducing energy needed liquid-liquid phase separation (LLPS). impact functions affecting mRNA surveillance activating Adenosine 5'-monophosphate (AMP)-activated kinase signaling, response. Our study highlights role LLPS nanomaterial metabolism suggests as potential targets drug delivery strategies, advancing field nanomedicine.

Language: Английский

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